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Preformulation Testing of Solid Dosage Forms :

Preformulation Testing of Solid Dosage Forms

Preformulation testing is the first step in the rational development of dosage forms of a drug substance. :

Preformulation testing is the first step in the rational development of dosage forms of a drug substance. It can be defined as an investigation of physical and chemical properties of a drug substance - alone and when combined with excipients.
The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced.

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During the early development of a new drug substance, the synthetic chemist, alone or in cooperation with specialists in other disciplines (including preformulation), may record some data which can be appropriately considered as preformulation data.
This early data collection may include such information as
- gross particle size,
- melting point,
- infrared analysis,
- thin-layer chromatographic purity,
- and other such characterizations of different laboratory-scale batches.
These data are useful in guiding, and becoming part of, the main body of preformulation work.

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The formal preformulation study should start at the point after biological screening, when a decision is made for further development of the compound in clinical trials.
Before embarking upon a formal program, the preformulation scientist must consider the following:
1. The available physicochemical data (including chemical structure, different salts available)
2. The therapeutic class of the compound and anticipated dose
3. The supply situation and the development schedule (i.e., the time available)
4. The availability of a stability-indicating assay
5. The nature of the information the formulator should have or would like to have

1. ORGANOLEPTIC PROPERTIES :

1. ORGANOLEPTIC PROPERTIES 1.1 Color
Unappealing to the eye ==> instrumental methods or variable from batch to batch
Record of early batches ==> establishing “specs” is very useful for later production
Undesirable or ==> incorporation of a dye variable color in the body or coating

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Cimetidine-acid hydrolysis

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OH- H+

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Techniques used for characterizing purity are the same as used in preformulation study :
- Thin layer chromatography (TLC)
- High-pressure liquid chromatography (HPLC)
- Gas chromatography (GC)
Impurity index (II) defined as the ratio of all responses (peak areas) due to components other than the main one to the total area response.
Homogeneity index (HI) defined as the ratio of the response (peak area) due to the main component to the total response.

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USP Impurity Index defined as a ratio of responses due to impurities to that response due to a defined concentration of a standard of the main component. (using TLC)
General limit 2 % impurities
All II, HI, USP II are not absolute measures of impurity since the specific response (molecular absorbances or extinction coefficient) due to each impurity is assumed to be the same as that of the main component.
More accurate analysis - identification of each individual impurity followed by preparation of standards for each one of them.

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(Undersize)

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(Undersize)

3.2 Determination of Surface Area :

3.2 Determination of Surface Area Surface areas of powders
-> increasing attention in recent years: reflect the particle size
Grinding operation:
particle size ==> surface area.
Brunauer-Emmett-Teller (BET) theory of adsorption
Most substances will adsorb a monomolecular layer of a gas under certain conditions of partial pressure (of the gas) and temperature.
Knowing the monolayer capacity of an adsorbent (i.e., the quantity of adsorbate that can be accommodated as a monolayer on the surface of a solid, the adsorbent) and the area of the adsorbate molecule, the surface area can, in principle be calculated.

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Most commonly, nitrogen is used as the adsorbate at a specific partial pressure established by mixing it with an inert gas, typically helium. The adsorption process is carried out at liquid nitrogen temperature (-195 oC).
It has been demonstrated that, at a partial pressure of nitrogen attainable when it is in a 30 % mixture with an inert gas and at -195 oC, a monolayer is adsorbed onto most solids.
Apparently, under these conditions the polarity of nitrogen is sufficient for van de Waals forces of attraction between the adsorbate and the adsorbents to be manifest.
The kinetic energy present under these conditions overwhelms the intermolecular attraction between nitrogen atoms. However, it is not sufficient to break the bonding between the nitrogen and dissimilar atoms. The latter are most often more polar and prone to van de Waals forces of attraction.
The nitrogen molecule does not readily enter into chemical combinations, and thus its binding is of a nonspecific nature (I.e., it enters into a physical adsorption); consequently , the nitrogen molecule is well suited for this role.

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The values of l (g of adsorbate/g of adsorbent) at various P values (partial pressure of the adsorbate gas) could be obtained from the experiment through instrument.
Po (vapor pressure of the pure adsorbate gas) can be obtained from the literature.
Plotting the term 1/[l(Po/P - 1)] against P/Po will obtain a straight line with
slope = (C - 1)/lmC
intercept = 1/lmC
The term C and lm can readily be obtained

Dynamic Method of Gas Adsorption :

Dynamic Method of Gas Adsorption Accurately weighing the sample into an appropriate container
Immersing the container in liquid nitrogen
Passing the gas over the sample
Removing the liquid nitrogen when the adsorption is complete (as signaled by the instrument)
Warming the sample to about the room temperature
Measuring (via the instrument) the adsorbated gas released (column 3 of Table 5)
Performing the calibration by injecting known amounts of adsorbated gas into the proper instrument port (column 4 and 5 of Table 5)
P is the product of the fraction of N2 in the gas mixture (column 1 of Table 5) and the ambient pressure

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At relatively large diameters, the specific surface area is insensitive to an increase in diameter
At very small diameters the surface area is comparatively very sensitive.
Relatively high surface area most often reflects a relatively small particle size, except porous or strongly agglomerated mass
Small particles (thus of high surface area) agglomerate more readily, and often to render the inner pores and surfaces inaccessible to dissolution medium

4. SOLUBILITY :

4. SOLUBILITY Solubility > 1 % w/v
=> no dissolution-related absorption problem
Highly insoluble drug administered in small doses may exhibit good absorption
Unstable drug in highly acidic environment of stomach, high solubility and consequent rapid dissolution could result in a decreased bioavailability
The solubility of every new drug must be determined as a function of pH over the physiological pH range of 1 - 8

4.1.3 Unique Problems in Solubility Determination of Poorly Soluble Compounds Solubilities could be overestimated due to the presence of soluble impurities
Saturation solubility is not reached in a reasonable length of time unless the amount of solid used is greatly in excess of that needed to saturation
Many compounds in solution degrade, thus making an accurate determination of solubility difficult
Difficulty is also encountered in the determination of solubility of metastable forms that transform to more stable forms when exposed to solvents

4.4 Solubilization :

4.4 Solubilization Drug not an acidic or basic, or the acidic or basic character not amendable to the formation of a stable salt
Use more soluble metastable polymorph
Use of complexation (eg. Ribloflavin-xanthines complex)
Use of high-energy coprecipitates that are mixtures of solid solutions and solid dispersions (eg. Griseofulvin in PEG 4000, 6000, and 20,000)
in PEG 4000 and 20,000 -> supersaturated solutions
in PEG 6000 -> bioavailability in human twice > micronized drug
Use of suitable surfactant

5.1.2.2 Nelson Constant Surface Method :

5.2 Particulate Dissolution :

5.2 Particulate Dissolution Particulate dissolution is used to study the influence on dissolution of particle size, surface area, and mixing with excipients.
The rate of dissolution normally increased with a decrease in the particle size.
Occasionally, however, an inverse relationship of particle size to dissolution is encountered.
This may be explained on the basis of effective or available, rather than absolute, surface area; and it is caused by incomplete wetting of the powder.
Incorporation of a surfactant in the dissolution medium may provide the expected relationship.

5.2.1 Effect of particle size of phenacetin on dissolution rate of the drug from granules :

5.2.2 Means of enhancing the slow dissolution: :

5.2.2 Means of enhancing the slow dissolution: in absence of more soluble physical or chemical form of the drug -
Particle size reduction (most commonly used).
Enhanced surface area by adsorbing the drug on an inert excipient with a high surface area, i.e., fumed silicon dioxide.
Comelting, coprecipitating, or triturating the drug with some excipients.
Incorporation of suitable surfactant.

5.3 Prediction of Dissolution Rate :

5.3 Prediction of Dissolution Rate Consider the dissolution of 22 mg of 60/80 mesh hydrocortisone in 500 ml of water. The aqueous solubility of hydrocortisone is 0.28 mg/ml. The 60/80 mesh fraction corresponds to 212 mm or 2.12x10-2 cm in diameter. The density of hydrocortisone is 1.25 g/ml. The volume of a sphere is (4/3)pr3. Assuming that all particles are spheres of the same diameter, 22 mg would correspond to
22 x 10-3 3 = 3,500 spherical particles
1.25 4p x (1.06)3 x 10-6
The area of a sphere is given by 4pr2. Therefore, the area of 3,500 particles of average radius 1.06x10-2 cm is
4p x (1.06)2 x 10-4 x 3,500 = 4.94 cm2

6. Parameter Affecting Absorption :

6. Parameter Affecting Absorption The absorption of drugs administered orally as solids consists of 2 consecutive processes:
1. The process of dissolution, followed by
2. The transport of the dissolved materials across gi membranes into systemic circulation

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The rate-determining step in the overall absorption process:
For relatively insoluble compounds
-> rate of dissolution
(can be altered via physical intervention)
For relatively soluble compounds
-> rate of permeation across biological membrane
(is dependent on size, relative aqueous and lipid solubilities, and ionic charge of the solute molecules)
(can be altered, in the majority of cases, only through molecular modification)

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In making a judgement concerning the absorption potential of a new drug entity, the preformulation scientist must undertake studies to delineate its dissolution as well as permeation behavior.
Characterization of the permeation behavior of a new drug must be performed at an early stage of drug development-primarily to help avoid mistaken efforts to improve its absorption by improving dissolution, when in reality the absorption is permeability-limited.
Permeability studies are of even greater importance when analogs of the compound having similar pharmacological attributes are available
Permeability studies then would aid in the selection of the compound with the greatest absorption potential.

6.1 Partition Coefficient :

6.1 Partition Coefficient Like biological membrane in general, the gi membranes are largely lipoidal in character.
The rate and extent of absorption decreased with the increasing polarity of molecules.
Partition coefficient (distribution coefficient): the ratio in which a solute distributes itself between the two phases of two immiscible liquids that are in contact with each other (mostly n-octanol/water).

Comparison Between Colonic Absorption and Lipid/Water Partition of the Un-ionized forms of Barbiturates :

6.2 Ionization Constant :

6.2 Ionization Constant The unionized species are more lipid-soluble and hence more readily absorbed.
The gi absorption of weakly acidic or basic drugs is related to the fraction of unionized drug in solution.
Factors affecting absorption:
- pH at the site of absorption
- Ionization constant
- Lipid solubility of unionized species
“pH-partition theory”